Iso-ergolines such as, for example, lisuride are established therapeutic agents for the treatment of migraine. More recently, a number of highly selective agents for the treatment of migraine which have high 5-HT1D: 5-HT1B binding ratios have been prepared, such as, for example, the alkyltryptamine derivatives (125-fold selectivity, Slassi, Bioorg. Med. Chem. Lett. 10: 1707-1709, (2000)), the indole series (300-fold selectivity, Castro, J. Med. Chem. 41: 2667 (1998)) and from the non-indole series (>6000 fold selectivity, Ennis, J. Med. Chem. 41: 2180 (1998)). However, strong agonism of 5-HT1B by migraine therapeutics such as, for example, sumatriptan (Phebus, Cephalalgia 17: 245 (1997)) frequently leads to adverse cardiovascular effects due to excessive vasoconstriction. Accordingly, an effective migraine agent should be selective for the 5-HT1D receptor over the 5-HT1B receptor, but with moderate agonism of the 5-HT1B receptor to minimize non-cranial vasoconstriction. Antagonism of adrenergic receptors, such as, for example, alpha1A, alpha1D, alpha2A, alpha2B and alpha2C by migraine therapeutics can reduce vasoconstriction caused by strong 5-HT1Bagonism. Additionally, for migraine prophylaxis, some compounds used for this indication exhibit 5-HT1A agonistic activity. In some embodiments, it may be advantageous for the agent to have 5-HT1A agonist activity.
Agonism of dopamine receptors is highly unfavorable for anti-migraine compounds since nausea is a classic dopaminergic (activation of dopamine receptors) symptom, which is already an indication of migraine itself. Yet another problem with many migraine derivatives is undesirable agonism of 5-HT2B receptors which is associated with cardiac and non-cardiac fibrosis, including cardiovascular valvulopathy (Rothman, Circulation 102: 2836 (2000)). Conversely, antagonism of 5-HT2B receptors may offer therapeutic advantages in the treatment and/or prevention of migraine (Schaerlinger, Br. J. Pharmacol. 140(2): 277-84, (2003)).
Accordingly, there is a continuing need for less toxic compounds to treat and/or prevent disorders such as, for example, migraine, which selectively agonize 5-HT1D receptors over 5-HT1B receptors with moderated 5-HT1B receptor agonism, have low dopamine receptor agonism and are 5-HT2B and adrenergic receptor antagonists. Furthermore, isoergolines, such as lisuride, for example, have the drawback of requiring frequent dosing which can lead to poor compliance and associated deficient disease control. Accordingly, there is also a need for compounds with greater circulating half life in the body to be used in treatment or prevention of disorders such as, for example, migraine.
Iso-ergolines, including lisuride, have also been established as effective anti-Parkinson's agents due to their agonist activities on dopaminergic and serotonin receptors. Typically, an ideal anti-Parkinson's agent will be a selective agonist for the dopaminergic D2 receptor. Weak to modest agonist activity on the serotonin 5-HT1B and/or 5-HT1D receptors is also desirable. Studies have also shown that 5-HT2 receptor antagonism may also be desirable for treatment of Parkinson's disease symptoms and/or for the reduction of undesirable side-effects such as cardiac or non-cardiac fibrosis and psychiatric side-effects (Newman-Tancredi et al., J. Pharmacology and Experimental Therapies 303(2): 815 (2002)). Depending on the treatment regimen, anti-Parkinson's agents may have a relatively short half-life (i.e., 1-5 hours) or a longer half-life (i.e., 20 hours or longer). Accordingly, there is a continuing need for less toxic and/or more effective compounds to treat and/or prevent disorders or symptoms associated with disorders such as, for example, Parkinson's disease.